Use of quinazoline derivatives for the treatment of viral diseases

ABSTRACT

The present invention relates to the use of quinazoline derivatives, which show EGFR inhibitory activity, for the prevention and/or treatment of virus-induced diseases, preferably virus induced respiratory diseases and exacerbation in chronic airway diseases such as COPD or asthma.

FIELD OF THE INVENTION

The present invention relates to the use of quinazoline derivatives,which show EGFR inhibitory activity, for the prevention and treatment ofvirus-induced diseases, preferably virus induced respiratory diseasesand exacerbations in chronic airway diseases such as COPD or asthma.

BACKGROUND OF THE INVENTION

Chronic airway diseases such as chronic bronchitis including COPD andasthma are characterized by inflammation and increased mucus production.Inflammation and excess mucus production are believed to drive theaccelerated decline of lung function in chronic airway diseases.

The increased mucus production is attributed to the remodelling of theairway epithelium in which ciliated cells have been replaced by mucusproducing goblet cells. The rarification of ciliated cells impairs themucociliary clearance. Together with the increased mucus production thisleads to mucus plugging of the small airways. An important function ofmucociliary clearance is to cleanse the airways from inhaledparticulates including viruses which have been trapped in the mucuslayer and are then removed from the airways together with the mucusthrough a coordinated movement of the cilia. In airway diseases such asCOPD and asthma, the viruses entrapped in mucus and stuck to the airwayepithelium encounter good conditions for infection. Viral infections ofthe lungs in patients with chronic airway diseases result in anexacerbation of the underlying disease, characterized by an aggravationof the symptoms such as excess mucus production, inflammation andairflow limitation. Patients with exacerbations often need to behospitalized because they suffer from a dramatic reduction of lungfunction. Further, in the long term, exacerbations lead to a more rapidand more progressive decline of lung functions compared to patients whodo not suffer from exacerbations. The major cause of exacerbations areviral infections of the airways and/or lungs.

It has been demonstrated that inhibition of the epidermal growth factorsignalling prevents the excess mucus production and increase in gobletcells. Recently it was shown that EGFR inhibitors can also preventand/or treat viral infections (WO 2005/048928; Liu Kenneth; Gualano RosaC; Hibbs Margaret L; Anderson Gary P; Bozinovski Steven Epidermal growthfactor receptor signaling to Erk1/2 and STATs control the intensity ofthe epithelial inflammatory responses to rhinovirus infection. TheJournal of Biological Chemistry (2008), 283(15), 9977-85; Monick M M.Cameron K. Staber J. Powers L S. Yarovinsky T O. Koland J G. HunninghakeG W. Activation of the epidermal growth factor receptor by respiratorysyncytial virus results in increased inflammation and delayed apoptosis.Journal of Biological Chemistry. 280(3):2147-58, 2005).

The present invention relates to the prevention and/or treatment ofviral infections and exacerbation in chronic airway diseases such asCOPD and asthma. Viral infections can be prevented or treated by EGFRinhibitors either by preventing entry of the virus, by inhibition ofvirus replication and/or by inhibition of symptoms caused by viralinfection. Inhibition of virus entry into the cells and/or replicationof the virus will reduce the viral load and reduce the severity andduration of an exacerbation. The inhibition of symptoms caused by viralinfection comprises inhibition/reduction of influx of inflammatory cellssuch as macrophages, neutrophils and lymphocytes, the inhibition of theupregulation of the EGF receptor and EGFR ligand, mucus production andinhibition/alleviation of the severity and duration of exacerbations.

It is the object of the present invention to provide an antiviral agent,i.e. an agent for treating and/or preventing viral infections or fortreating and/or preventing exacerbation in chronic airway diseases suchas COPD and asthma.

DESCRIPTION OF THE INVENTION

Surprisingly it has been found, that the EGFR inhibitors of the presentinvention that had been optimized for inhibition of mucus production andincrease of mucus producing goblet cells also demonstrate very potentanti-viral effects.

Accordingly the invention provides the use of an EGFR inhibitor ofgeneral formula (I)

whereinR^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group,R^(b) denotes a phenyl or 1-phenylethyl group, wherein the phenylnucleus is substituted in each case by the groups R¹ to R³, while

-   -   R¹ and R², which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynyl        group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a heteroaryl, heteroaryloxy, heteroarylmethyl or        heteroarylmethoxy group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms        or    -   a cyano, nitro or amino group, and    -   R³ denotes a hydrogen, fluorine, chlorine or bromine atom or    -   a methyl or trifluoromethyl group,        R^(c) denotes a cyclobutyl, cyclopentyl or cyclohexyl group        which is substituted in each case by a group R⁴—N—R⁵, while    -   R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and    -   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,    -   an aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl,        piperidin-1-ylcarbonyl-C₁₋₃-alkyl,        homopiperidin-1-ylcarbonyl-C₁₋₃-alkyl,        morpholin-4-ylcarbonyl-C₁₋₃-alkyl,        homomorpholin-4-ylcarbonyl-C₁₋₃-alkyl,        piperazin-1-ylcarbonyl-C₁₋₃-alkyl,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl-C₁₋₃-alkyl,        homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl or a        4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl group,    -   a hydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,        C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,        C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,        C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl,        aminocarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,        di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,        pyrrolidin-1-ylcarbonylamino-C₂₋₄-alkyl,        piperidin-1-ylcarbonylamino-C₂₋₄-alkyl,        morpholin-4-ylcarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylsulphonyl-C₂₋₄-alkyl or a        C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group,    -   a (2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl,        (2-oxopiperidin-1-yl)-C₂₋₄-alkyl,        (3-oxo-morpholin-4-yl)-C₂₋₄-alkyl,        (2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or a        (2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group,    -   a C₁₋₄-alkylsulphonyl, chloro-C₁₋₄-alkylsulphonyl,        bromo-C₁₋₄-alkylsulphonyl, amino-C₁₋₄-alkylsulphonyl,        C₁₋₃-alkylamino-C₁₋₄-alkylsulphonyl,        di-(C₁₋₃-alkyl)amino-C₁₋₄-alkylsulphonyl,        (pyrrolidin-1-yl)-C₁₋₄-alkylsulphonyl,        (piperidin-1-yl)-C₁₋₄-alkylsulphonyl,        (homopiperidin-1-yl)-C₁₋₄-alkylsulphonyl,        (morpholin-4-yl)-C₁₋₄-alkylsulphonyl,        (homomorpholin-4-yl)-C₁₋₄-alkylsulphonyl,        (piperazin-1-yl)-C₁₋₄-alkylsulphonyl,        (4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkylsulphonyl,        (homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl or a        (4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl group,    -   a C₁₋₄-alkyloxycarbonyl group,    -   a formyl, C₁₋₄-alkyl-carbonyl,        C₁₋₃-alkyloxy-C₁₋₄-alkyl-carbonyl, tetrahydrofuranylcarbonyl,        tetrahydropyranylcarbonyl, amino-C₁₋₄-alkyl-carbonyl,        C₁₋₃-alkylamino-C₁₋₄-alkyl-carbonyl,        di-(C₁₋₃-alkyl)amino-C₁₋₄-alkyl-carbonyl,        pyrrolidin-1-yl-C₁₋₄-alkyl-carbonyl,        piperidin-1-yl-C₁₋₄-alkyl-carbonyl,        (homopiperidin-1-yl)-C₁₋₄-alkyl-carbonyl,        morpholin-4-yl-C₁₋₄-alkyl-carbonyl,        (homomorpholin-4-yl)-C₁₋₄-alkyl-carbonyl,        (piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl or a        C₁₋₃-alkylsulphonyl-C₁₋₄-alkyl-carbonyl group,    -   a cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)amino-carbonyl,        (C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        N—(C₁₋₃-alkyl)-N—(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        arylaminocarbonyl, pyrrolidin-1-ylcarbonyl,        piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl,        morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,        piperazin-1-ylcarbonyl, 4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl,        homopiperazin-1-ylcarbonyl,        4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl, aminosulphonyl,        C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,        pyrrolidin-1-ylsulphonyl, piperidin-1-ylsulphonyl,        homopiperidin-1-ylsulphonyl, morpholin-4-ylsulphonyl,        homomorpholin-4-ylsulphonyl, piperazin-1-ylsulphonyl,        4-C₁₋₃-alkyl-piperazin-1-ylsulphonyl,        homopiperazin-1-ylsulphonyl or a        4-C₁₋₃-alkyl-homopiperazin-1-ylsulphonyl group,        a cyclobutyl, cyclopentyl or cyclohexyl group which is        substituted in each case by a group R⁶, where    -   R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,        3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,        2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl,        2-oxo-hexahydropyrimidin-1-yl or a        2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl group,        an azetidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a pyrrolidin-3-yl group which is substituted in the 1 position        by the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-4-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or        tetrahydropyran-4-yl group,        R^(d) denotes a hydrogen atom or a fluorine, chlorine or bromine        atom,        a hydroxy group,        a C₁₋₄-alkyloxy group,        a methoxy group substituted by 1 to 3 fluorine atoms,        an ethyloxy group substituted by 1 to 5 fluorine atoms,        a C₂₋₄-alkyloxy group which is substituted by a group R⁶ or R⁷,        while    -   R⁶ is as hereinbefore defined and    -   R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,        homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,        4-C₁₋₃-alkyl-piperazin-1-yl, homopiperazin-1-yl or        C₁₋₃-alkyl-homopiperazin-1-yl group, or    -   a formylamino, C₁₋₄-alkylcarbonylamino,        C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino,        C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,        C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,        piperazin-1-ylcarbonylamino,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino,        morpholin-4-ylcarbonylamino or a C₁₋₄-alkylsulphonylamino group,        a C₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group,        a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or        tetrahydropyran-4-yloxy group,        a tetrahydrofuranyl-C₁₋₄-alkyloxy or        tetrahydropyranyl-C₁₋₄-alkyloxy group,        a C₁₋₄-alkoxy group which is substituted by a pyrrolidinyl,        piperidinyl or homopiperidinyl group substituted in the 1        position by the group R⁸, while    -   R⁸ denotes a hydrogen atom or a C₁₋₃-alkyl group,        or a C₁₋₄-alkoxy group which is substituted by a morpholinyl        group substituted in the 4 position by the group R⁸, while R⁸ is        as hereinbefore defined, and        X denotes a methyne group substituted by a cyano group or a        nitrogen atom, and        by the aryl groups mentioned in the definition of the above        groups is meant in each case a phenyl group which is mono- or        disubstituted by R⁹, while the substituents may be identical or        different and    -   R⁹ denotes a hydrogen atom, a fluorine, chlorine, bromine or        iodine atom or a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy or cyano group,        by the heteroaryl groups mentioned in the definition of the        above groups is meant a pyridyl, pyridazinyl, pyrimidinyl or        pyrazinyl group, while the abovementioned heteroaryl groups are        each mono- or disubstituted by the group R⁹, while the        substituents may be identical or different and R⁹ is as        hereinbefore defined, and        the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and        morpholinyl groups may be substituted in each case by one or two        C₁₋₃-alkyl groups, and        unless otherwise stated, the abovementioned alkyl groups may be        straight-chained or branched,        their tautomers, their stereoisomers, their mixtures and their        salts,        or        the use of an EGFR inhibitor of general formula (II)

whereinR_(a) denotes a benzyl or 1-phenylethyl group or a phenyl groupsubstituted by the groups R₁ and R₂, wherein

-   -   R₁ denotes a hydrogen, fluorine, chlorine or bromine atom, a        methyl, trifluoromethyl, cyano or ethynyl group and    -   R₂ denotes a hydrogen or fluorine atom,        one of the groups R_(b) or R_(c) denotes an R₃—(CH₂)_(m)—O group        and the other group R_(b) or R_(c) denotes a methoxy,        cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,        cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy,        tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,        tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,        where    -   R₃ denotes an N-(2-oxo-tetrahydrofuran-4-yl)-methylamino or        N-(2-oxo-tetrahydrofuran-4-yl)-ethylamino group,    -   an R₄—O—CO—CH₂—N—CH₂CH₂—OH group substituted at the methylene        groups by one or two methyl or ethyl groups, wherein        -   R₄ represents a hydrogen atom or a C₁₋₄-alkyl group,    -   or a 2-oxo-morpholin-4-yl group substituted by one or two methyl        or ethyl groups and    -   m denotes the number 2, 3 or 4,        the tautomers, the stereoisomers and the salts thereof,        or        the use of an EGFR inhibitor of general formula (III)

whereinR^(a) denotes a phenyl, 1-phenylethyl or indan-4-yl group, wherein thephenyl nucleus is substituted in each case by the groups R¹ to R³,wherein

-   -   R¹ and R², which may be identical or different, each denote a        hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynyl        group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a heteroaryl, heteroaryloxy, heteroarylmethyl or        heteroarylmethoxy group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms        or    -   a cyano, nitro or amino group, and    -   R³ denotes a hydrogen, fluorine, chlorine or bromine atom or    -   a methyl or trifluoromethyl group,        R^(b) denotes an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,        homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,        piperazin-1-yl, 4-(C₁₋₄-alkyl-carbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyl-sulphonyl)-piperazin-1-yl, homopiperazin-1-yl,        4-(C₁₋₄-alkyl-carbonyl)-homopiperazin-1-yl or        4-(C₁₋₄-alkyl-sulphonyl)-homopiperazin-1-yl group which may be        mono-, di- or trisubstituted by R⁴ in each case, while the        substituents may be identical or different and    -   R⁴ denotes a fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms,    -   an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino,        C₁₋₄-alkyl-carbonylamino,        N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-carbonylamino,        C₁₋₄-alkyl-sulphonylamino or        N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-sulphonylamino group,    -   an amino-C₁₋₄-alkyl, C₁₋₄-alkylamino-C₁₋₄-alkyl,        di-(C₁₋₄-alkyl)amino-C₁₋₄-alkyl,        C₁₋₄-alkyl-carbonylamino-C₁₋₄-alkyl,        N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-carbonylamino-C₁₋₄-alkyl,        C₁₋₄-alkyl-sulphonylamino-C₁₋₄-alkyl or        N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-sulphonylamino-C₁₋₄-alkyl group,    -   a hydroxy, C₁₋₄-alkyloxy or C₁₋₄-alkyl-carbonyloxy group    -   a hydroxy-C₁₋₄-alkyl, C₁₋₄-alkyloxy-C₁₋₄-alkyl or        C₁₋₄-alkyl-carbonyloxy-C₁₋₄-alkyl group,    -   a C₁₋₄-alkyl-carbonyl, cyano, C₁₋₄-alkyl-oxycarbonyl, carboxy,        aminocarbonyl,    -   C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)amino-carbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-C₁₋₄-alkyl-piperazin-1-yl-carbonyl or        morpholin-4-yl-carbonyl group,    -   a C₁₋₄-alkylcarbonyl-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,        C₁₋₄-alkyloxycarbonyl-C₁₋₄-alkyl, aminocarbonyl-C₁₋₄-alkyl,        C₁₋₄-alkylaminocarbonyl-C₁₋₄-alkyl,        di-(C₁₋₄-alkyl)aminocarbonyl-C₁₋₄-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl,        piperidin-1-yl-carbonyl-C₁₋₄-alkyl,        piperazin-1-yl-carbonyl-C₁₋₄-alkyl,        4-C₁₋₄-alkyl-piperazin-1-yl-carbonyl-C₁₋₄-alkyl or        morpholin-4-yl-carbonyl-C₁₋₄-alkyl group,    -   a C₁₋₄-alkylsulphanyl, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,        aminosulphonyl, C₁₋₄-alkyl-aminosulphonyl or        di-(C₁₋₄-alkyl)amino-sulphonyl group,    -   a C₁₋₄-alkylsulphanyl-C₁₋₄-alkyl,        C₁₋₄-alkylsulphinyl-C₁₋₄-alkyl, C₁₋₄-alkylsulphonyl-C₁₋₄-alkyl,        aminosulphonyl-C₁₋₄-alkyl, C₁₋₄-alkyl-aminosulphonyl-C₁₋₄-alkyl        or di-(C₁₋₄-alkyl)amino-sulphonyl-C₁₋₄-alkyl group    -   and wherein the heterocycles mentioned under R^(b) above may        additionally be substituted by an oxo group,        R^(c) denotes a hydrogen atom,        a fluorine, chlorine, bromine or iodine atom,        a C₁₋₄-alkyl group,        a C₁₋₄-alkyl group which is substituted by an R⁵ group, where    -   R⁵ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,        homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,        2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,        4-C₁₋₃-alkyl-piperazin-1-yl, homopiperazin-1-yl or        C₁₋₃-alkyl-homopiperazin-1-yl group or    -   a formylamino, C₁₋₄-alkylcarbonylamino,        C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino,        C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,        C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,        piperazin-1-ylcarbonylamino,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino,        morpholin-4-ylcarbonylamino or a C₁₋₄-alkylsulphonylamino group,        a hydroxy group,        a C₁₋₄-alkyloxy group,        a methoxy or ethyloxy group substituted by 1 to 3 fluorine        atoms,        a C₂₋₄-alkyloxy group which is substituted by the group R⁵,        where R⁵ is as hereinbefore defined,        a C₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group,        a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or        tetrahydropyran-4-yloxy group,        a tetrahydrofuranyl-C₁₋₄-alkyloxy or        tetrahydropyranyl-C₁₋₄-alkyloxy group,        a C₁₋₄-alkoxy group which is substituted by a pyrrolidinyl,        piperidinyl or homopiperidinyl group substituted in the 1        position by the group R⁶, where    -   R⁶ denotes a hydrogen atom or a C₁₋₃-alkyl group,        or a C₁₋₄-alkoxy group which is substituted by a morpholinyl        group substituted in the 4 position by the group R⁶, where R⁶ is        as hereinbefore defined, and wherein the pyrrolidinyl,        piperidinyl, piperazinyl and morpholinyl groups mentioned above        in the definition of the group R^(c) may each be substituted by        one or two C₁₋₃-alkyl groups, and        wherein by the aryl groups mentioned in the definition of the        foregoing groups is meant in each case a phenyl group which is        mono- or disubstituted by R⁷, wherein the substituents may be        identical or different and    -   R⁷ denotes a hydrogen atom, a fluorine, chlorine, bromine or        iodine atom or a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy or cyano group, and        by the heteroaryl groups mentioned in the definition of the        foregoing groups is meant a pyridyl, pyridazinyl, pyrimidinyl or        pyrazinyl group, wherein the above-mentioned heteroaryl groups        are mono- or disubstituted by the group R⁷, wherein the        substituents may be identical or different and R⁷ is as        hereinbefore defined, and        unless stated otherwise, the above-mentioned alkyl groups may be        straight-chain or branched, the tautomers, the stereoisomers,        the mixtures thereof and salts thereof,        or        the use of an EGFR inhibitor of general formula (IV)        Compounds of General Formula (I)

characterised in thatR^(a) denotes a phenyl or 1-phenylethyl group, wherein the phenylnucleus is substituted in each case by the groups R¹ to R³, wherein

-   -   R¹ and R² which may be identical or different, denote hydrogen        or        -   a group selected from among        -   F, Cl, Br, I, OCH₂F, OCHF₂, OCF₃, CH₂F, CHF₂, CF₃, CN, NO₂,            NH₂ and OH,    -   or        -   a group selected from among        -   C₁₋₄-alkyl, C₁₋₄-alkyl-O, C₂₋₃-alkenyl, C₂₋₃-alkynyl,            phenyl, phenyl-O, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl-O,            heteroaryl, heteroaryl-O, heteroaryl-C₁₋₃-alkyl,            heteroaryl-C₁₋₃-alkyl-O, while the above-mentioned phenyl            groups are mono- or disubstituted by groups R⁵,    -   and    -   R³ denotes hydrogen,        -   or        -   a group selected from among        -   F, Cl, Br and CH₃,            R^(b) denotes hydrogen, or a group, optionally substituted,            selected from among C₁₋₆-alkyl, C₃₋₆-cycloalkyl- and            C₃₋₆-cycloalkyl-C₁₋₃-alkyl,            R^(c) denotes hydrogen, or an optionally substituted group            selected from among C₁₋₆-alkyl, C₃₋₆-cycloalkyl,            C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₁₋₆-alkyl-CO,            C₃₋₆-cycloalkyl-CO, C₃₋₆-cycloalkyl-C₁₋₃-alkyl-CO,            C₁₋₆-alkyl-SO₂, C₃₋₆-cycloalkyl-SO₂,            C₃₋₆-cycloalkyl-C₁₋₃-alkyl-SO₂, phenyl-CO— and phenyl-SO₂,            R^(d) denotes hydrogen or    -   a group selected from among    -   F, Cl, Br, I, OH, C₁₋₄-alkyl, C₁₋₄-alkyl-O, C₁₋₂-alkyl-O        substituted by 1 to 3 fluorine atoms, C₃₋₇-cycloalkyl-O,        C₃₋₇-cycloalkyl-C₁₋₄-alkyl-O, tetrahydrofuran-3-yl-O,        tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O,        tetrahydrofuranyl-C₁₋₄-alkyl-O— and        tetrahydropyranyl-C₁₋₄-alkyl-O,        or    -   R⁴—C₁₋₄-alkyl, while the linking of the groups R⁴ may take place        via each C atom of the alkyl group,        or    -   R⁴—C₂₋₄-alkyl-O, wherein the group R⁴ is separated from the        oxygen atom by at least 2 C atoms,        or    -   a group selected from among    -   pyrrolidin-2-yl-C₁₋₄-alkyl-O, pyrrolidin-3-yl-C₁₋₄-alkyl-O,        piperidin-2-yl-C₁₋₄-alkyl-O, piperidin-3-yl-C₁₋₄-alkyl-O,        piperidin-4-yl-C₁₋₄-alkyl-O, azepan-2-yl-C₁₋₄-alkyl-O,        azepan-3-yl-C₁₋₄-alkyl-O, azepan-4-yl-C₁₋₄-alkyl-O,        morpholin-2-yl-C₁₋₄-alkyl-O, morpholin-3-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-pyrrolidin-2-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-pyrrolidin-3-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-piperidin-2-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-piperidin-3-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-piperidin-4-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-azepan-2-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-azepan-3-yl-C₁₋₄-alkyl-O,        1-(C₁₋₃-alkyl)-azepan-4-yl-C₁₋₄-alkyl-O,        4-(C₁₋₃-alkyl)-morpholin-2-yl-C₁₋₄-alkyl-O— and        4-(C₁₋₃-alkyl)-morpholin-3-yl-C₁₋₄-alkyl-O,    -   while    -   R⁴ denotes a group, which may be identical or different,        selected from among        -   OH, C₁₋₃-alkyl-O, C₃₋₆-cycloalkyl-O, NH₂, C₁₋₃-alkyl-NH,            (C₁₋₃-alkyl)₂N, (2-methoxyethyl)₂N, pyrrolidin-1-yl,            piperidin-1-yl, azepan-1-yl, morpholin-4-yl,            1,4-oxazepan-4-yl, 2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl,            3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,            8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,            4-(C₁₋₃-alkyl)-piperazin-1-yl, 1,4-diazepan-1-yl,            4-(C₁₋₃-alkyl)-1,4-diazepan-1-yl, HCO—NH, C₁₋₄-alkyl-CO—NH,            C₁₋₃-alkyl-O—C₁₋₃-alkyl-CO—NH, C₁₋₄-alkyl-O—CO—NH, H₂NCONH,            C₁₋₃-alkyl-NH—CO—NH, (C₁₋₃-alkyl)₂N—CONH,            pyrrolidin-1-yl-CO—NH, piperidin-1-yl-CO—NH,            piperazin-1-yl-CO—NH, 4-(C₁₋₃-alkyl)-piperazin-1-yl-CO—NH,            morpholin-4-yl-CO—NH— and C₁₋₄-alkyl-SO₂—NH,            while the pyrrolidinyl, piperidinyl, azepan-1-yl,            piperazinyl, 1,4-diazepan-1-yl, morpholinyl- and            1,4-oxazepan-4-yl groups mentioned above in the definition            of the group R^(d) may each additionally be substituted by            one or two C₁₋₃-alkyl groups, and            wherein the above-mentioned phenyl groups are mono- or            disubstituted by groups R⁵, wherein    -   R⁵ denotes hydrogen, or        -   a group, which may be identical or different, selected from            among        -   F, Cl, Br, I, OH, CN, C₁₋₃-alkyl, C₁₋₃-alkyl-O, CHF₂, CF₃,            —O—CHF₂ and —O—CF₃,            and            unless stated otherwise, the above-mentioned alkyl groups            may be straight-chain or to branched,            A denotes —CO or —C₁-C₃-alkylene,    -   while the —C₁-C₃-alkylene-group may be 1-, 2-, 3- or        4-substituted by a group R⁶,        and    -   R⁶ which may be identical or different, denotes hydrogen, or        -   a group selected from among OH, C₁-C₄-alkyl and            —O—C₁-C₄-alkyl            optionally in the form of the tautomers, the racemates, the            enantiomers, the diastereomers and the mixtures thereof, and            optionally the pharmacologically acceptable acid addition            salts, solvates and hydrates thereof.            for the manufacture of a medicament for the treatment of            virus-induced diseases.            The invention also provides the use of an EGFR inhibitor            selected from a group consisting of

-   (1.1)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

-   (1.2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dim    ethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,

-   (1.3)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (1.4)    4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (1.5)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

-   (1.6)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.7)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.8)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,

-   (1.9)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.10)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.11)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.12)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,

-   (1.13)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

-   (1.14)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline

-   (1.15)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,

-   (1.16)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,

-   (1.17)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

-   (1.18)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

-   (1.19)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

-   (1.20)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,

-   (1.21)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methan-sulfonylamino-ethoxy)-quinazoline,

-   (1.22)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.23)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.24)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.25)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.26)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.27)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.28)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,

-   (1.29)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,

-   (1.30)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,

-   (1.31)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.32)    4-[(3-ethinyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

-   (1.33)    4-[(3-ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,

-   (1.34)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.35)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.36)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

-   (1.37)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.38)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,

-   (1.39)    4-[(3-ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.40)    4-[(3-ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.41)    4-[(3-ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.42)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,

-   (1.43)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.44)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.45)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

-   (1.46)    4-[(3-ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.47)    4-[(3-ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

-   (1.48)    4-[(3-ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.49)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.50)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.51)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.52)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.53)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.54)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.55)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.56)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,

-   (1.57)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,

-   (1.58)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.59)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,

-   (1.60)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.61)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   (1.62)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.63)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxo-hexahydropyrimidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.64)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (1.65)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.66)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.67)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline,

-   (1.68)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.69)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

-   (1.70)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

-   (1.71)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-quinazoline,

-   (1.72)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(morpholin-4-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.73)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(morpholin-4-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.74)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[(R)-cis-4-(3-hydroxy-pyrrolidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.75)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[(R)-trans-4-(3-hydroxy-pyrrolidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.76)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.77)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.78)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[(S)-cis-4-(3-hydroxy-pyrrolidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.79)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[(S)-trans-4-(3-hydroxy-pyrrolidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.80)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-{(S)-cis-4-[2-(aminocarbonyl)-pyrrolidin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline,

-   (1.81)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-{(S)-trans-4-[2-(aminocarbonyl)-pyrrolidin-1-yl]-cyclohexyloxy}-7-methoxy-quinazoline,

-   (1.82)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-hydroxy-piperidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.83)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-hydroxy-piperidin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.84)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,    and

-   (1.85)    4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

-   (1.86)    anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one

-   (1.87)    syn-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one

-   (1.88)    anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-methyl-1,4-diaza-spiro[5.5]undecan-5-one

-   (1.89)    anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-dimethyl-1,4-diaza-spiro[5.5]undecan-5-one

-   (1.90)    anti-8-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,3-diaza-spiro[4.5]decan-2,4-dione

-   (1.91)    syn-8-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,3-diaza-spiro[4.5]decan-2,4-dione    -   optionally in the form of tautomers, racemates, enantiomers,        diastereomers, pharmacologically acceptable acid addition salts,        solvates or hydrates thereof,        for the manufacture of a medicament for the treatment of        virus-induced diseases.

Preferably the present invention relates to the said use wherein thevirus-induced disease is a respiratory disease.

Further preferred is the use of therapeutically effective amounts of thecompounds for the treatment of virus-induced exacerbation of arespiratory disease.

Further preferred is the said use, wherein the respiratory disease isselected from the group consisting of asthma, chronic obstructivepulmonary disease (COPD), chronic bronchitis, otitis media, sinusitis,pneumonia, lung fibrosis and cystic fibrosis, preferably asthma, chronicobstructive pulmonary disease (COPD) and chronic bronchitis, mostpreferably COPD.

Further preferred is said use, wherein the treatment is by airwaydelivery.

Further preferred is said use, wherein said treatment is by oraldelivery.

Further preferred is said use, wherein said virus is selected from thegroup consisting of Rhinovirus, influenza virus, parainfluenza virus,coronavirus, adenovirus, respiratory syncytial virus, picornavirus,metapneumovirus, hantavirus, measles virus, Epstein-Barr virus, herpessimplex virus, cytomegalovirus, Rhinovirus, influenza virus,parainfluenza virus, coronavirus, adenovirus, respiratory syncytialvirus, picornavirus and metapneumovirus, preferably influenza virus,rhinovirus, respiratory syncytial virus, adenovirus, parainfluenzavirus, corona virus, picornavirus and metapneumovirus, more preferablyinfluenza virus, rhinovirus, respiratory syncytial virus, adenovirus andparainfluenza virus, most preferably influenza virus, rhinovirus andrespiratory syncytial virus.

The EGFR inhibitors (1.1) to (1.85) can be administered in combinationwith one or more active agents, e.g. other EGFR inhibitors, antibiotics,antiviral agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAPkinase inhibitors, NK₁ antagonists, anticholinergics and endothelinantagonists.

The EGFR inhibitors will be preferentially administered once or twicedaily in a dose range of 0.001-10 mg, when administered via inhalationor in a dose range of 0.5-100 mg when administered via the oral route

The invention claimed is:
 1. A method for the treatment of viralinfection and exacerbation in respiratory diseases comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (IV)

wherein: R^(a) denotes a phenyl or 1-phenylethyl group, wherein thephenyl nucleus is substituted in each case by the groups R¹ to R³,wherein R¹ and R² which may be identical or different, denote hydrogenor a group selected from among F, Cl, Br, I, OCH₂F, OCHF₂, OCF₃, CH₂F,CHF₂, CF₃, CN, NO₂, NH₂ and OH, or a group selected from amongC₁₋₄-alkyl, C₁₋₄-alkyl-O, C₂₋₃-alkenyl, C₂₋₃-alkynyl, phenyl, phenyl-O,phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl-O, heteroaryl, heteroaryl-O,heteroaryl-C₁₋₃-alkyl, heteroaryl-C₁₋₃-alkyl-O, while theabove-mentioned phenyl groups are mono- or disubstituted by groups R⁵,and R³ denotes hydrogen, or a group selected from among F, Cl, Br andCH₃, R^(b) denotes hydrogen, or a group, optionally substituted,selected from among C₁₋₆-alkyl, C₃₋₆-cycloalkyl- andC₃₋₆-cycloalkyl-C₁₋₃-alkyl, R^(c) denotes hydrogen, or an optionallysubstituted group selected from among C₁₋₆-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₁₋₆-alkyl-CO, C₃₋₆-cycloalkyl-CO,C₃₋₆-cycloalkyl-C₁₋₃-alkyl-CO, C₁₋₆-alkyl-SO₂, C₃₋₆-cycloalkyl-SO₂,C₃₋₆-cycloalkyl-C₁₋₃-alkyl-SO₂, phenyl-CO— and phenyl-SO₂, R^(d) denoteshydrogen or a group selected from among F, Cl, Br, I, OH, C₁₋₄-alkyl,C₁₋₄-alkyl-O, C₁₋₂-alkyl-O substituted by 1 to 3 fluorine atoms,C₃₋₇-cycloalkyl-O, C₃₋₇-cycloalkyl-C₁₋₄-alkyl-O, tetrahydrofuran-3-yl-O,tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O,tetrahydrofuranyl-C₁₋₄-alkyl-O— and tetrahydropyranyl-C₁₋₄-alkyl-O, orR⁴—C₁₋₄-alkyl, while the linking of the groups R⁴ may take place viaeach C atom of the alkyl group, or R⁴—C₂₋₄-alkyl-O, wherein the group R⁴is separated from the oxygen atom by at least 2 C atoms, or a groupselected from among pyrrolidin-2-yl-C₁₋₄-alkyl-O,pyrrolidin-3-yl-C₁₋₄-alkyl-O, piperidin-2-yl-C₁₋₄-alkyl-O,piperidin-3-yl-C₁₋₄-alkyl-O, piperidin-4-yl-C₁₋₄-alkyl-O,azepan-2-yl-C₁₋₄-alkyl-O, azepan-3-yl-C₁₋₄-alkyl-O,azepan-4-yl-C₁₋₄-alkyl-O, morpholin-2-yl-C₁₋₄-alkyl-O,morpholin-3-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-pyrrolidin-2-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-pyrrolidin-3-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-piperidin-2-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-piperidin-3-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-piperidin-4-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-azepan-2-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-azepan-3-yl-C₁₋₄-alkyl-O,1-(C₁₋₃-alkyl)-azepan-4-yl-C₁₋₄-alkyl-O,4-(C₁₋₃-alkyl)-morpholin-2-yl-C₁₋₄-alkyl-O— and4-(C₁₋₃-alkyl)-morpholin-3-yl-C₁₋₄-alkyl-O, while R⁴ denotes a group,which may be identical or different, selected from among OH,C₁₋₃-alkyl-O, C₃₋₆-cycloalkyl-O, NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,(2-methoxyethyl)₂N, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl,morpholin-4-yl, 1,4-oxazepan-4-yl, 2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl,piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl, 1,4-diazepan-1-yl,4-(C₁₋₃-alkyl)-1,4-diazepan-1-yl, HCO—NH, C₁₋₄-alkyl-CO—NH,C₁₋₃-alkyl-O—C₁₋₃-alkyl-CO—NH, C₁₋₄-alkyl-O—CO—NH, H₂NCONH,C₁₋₃-alkyl-NH—CO—NH, (C₁₋₃-alkyl)₂N—CONH, pyrrolidin-1-yl-CO—NH,piperidin-1-yl-CO—NH, piperazin-1-yl-CO—NH,4-(C₁₋₃-alkyl)-piperazin-1-yl-CO—NH, morpholin-4-yl-CO—NH— andC₁₋₄-alkyl-SO₂—NH, while the pyrrolidinyl, piperidinyl, azepan-1-yl,piperazinyl, 1,4-diazepan-1-yl, morpholinyl- and 1,4-oxazepan-4-ylgroups mentioned above in the definition of the group R^(d) may eachadditionally be substituted by one or two C₁₋₃-alkyl groups, and whereinthe above-mentioned phenyl groups are mono- or disubstituted by groupsR⁵, wherein R⁵ denotes hydrogen, or a group, which may be identical ordifferent, selected from among F, Cl, Br, I, OH, CN, C₁₋₃-alkyl,C₁₋₃-alkyl-O, CHF₂, CF₃, —O—CHF₂ and —O—CF₃, and unless statedotherwise, the above-mentioned alkyl groups may be straight-chain orbranched, A denotes —CO or —C₁-C₃-alkylene, while the—C₁-C₃-alkylene-group may be 1-, 2-, 3- or 4-substituted by a group R⁶,and R⁶ which may be identical or different, denotes hydrogen, or a groupselected from among OH, C₁-C₄-alkyl and —O—C₁-C₄-alkyl or a tautomer,stereoisomer, mixture, or salt thereof.
 2. A method for the treatment ofviral infection and exacerbation in respiratory diseases comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound selected from the group consisting of (1.86)anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one,(1.87)syn-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one,(1.88)anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-methyl-1,4-diaza-spiro[5.5]undecan-5-one,(1.89)anti-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-dimethyl-1,4-diaza-spiro[5.5]undecan-5-one,(1.90)anti-8-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,3-diaza-spiro[4.5]decan-2,4-dione,(1.91)syn-8-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,3-diaza-spiro[4.5]decan-2,4-dione,and the tautomers, racemates, enantiomers, diastereomers andpharmacologically acceptable acid addition salts thereof.
 3. The methodaccording to claim 1, wherein the respiratory disease is selected fromthe group consisting of asthma, chronic obstructive pulmonary disease(COPD), chronic bronchitis, otitis media, sinusitis, pneumonia, lungfibrosis and cystic fibrosis.
 4. The method according to claim 1,wherein said treatment is by airway delivery.
 5. The method according toclaim 1, wherein said treatment is by oral delivery.
 6. The methodaccording to claim 1, wherein said virus is selected from the groupconsisting of Rhinovirus, influenza virus, parainfluenza virus,coronavirus, adenovirus, respiratory syncytial virus, picornavirus,metapneumovirus, hantavirus, measles virus, Epstein-Barr virus, herpessimplex virus and cytomegalovirus.